Caenorhabditis elegans has emerged as a major model in biomedical and environmental toxicology. Numerous papers on toxicology and pharmacology in C. elegans have been published, and this species has now been adopted by investigators in academic toxicology, pharmacology, and drug discovery labs. C. elegans has also attracted the interest of governmental regulatory agencies charged with evaluating the safety of chemicals. However, a major, fundamental aspect of toxicological science remains underdeveloped in C. elegans: xenobiotic metabolism and transport processes that are critical to understanding toxicokinetics and toxicodynamics, and extrapolation to other species. The aim of this review was to initially briefly describe the history and trajectory of the use of C. elegans in toxicological and pharmacological studies. Subsequently, physical barriers to chemical uptake and the role of the worm microbiome in xenobiotic transformation were described. Then a review of what is and is not known regarding the classic Phase I, Phase II, and Phase III processes was performed. In addition, the following were discussed (1) regulation of xenobiotic metabolism; (2) review of published toxicokinetics for specific chemicals; and (3) genetic diversity of these processes in C. elegans. Finally, worm xenobiotic transport and metabolism was placed in an evolutionary context; key areas for future research highlighted; and implications for extrapolating C. elegans toxicity results to other species discussed.

https://www.tandfonline.com/doi/pdf/10.1080/10937404.2021.1884921

Xenobiotic metabolism and transport in Caenorhabditis elegans

Synthesis and characterization of polyethylene terephthalate (PET) precursors and potential degradation products: Toxicity study and application in discovery of novel PETases

Caenorhabditis elegans for predictive toxicology

/pdf/the-eu-chemicals-strategy-for-sustainability-questions-qd7wkont1g.pdf

The "EU chemicals strategy for sustainability" questions regulatory toxicology as we know it: is it all rooted in sound scientific evidence?

Biologically active environmental pollutants have significant impact on ecosystems, wildlife, and human health. Microplastic (MP) and nanoplastic (NP) particles are pollutants that are present in the terrestrial and aquatic ecosystems at virtually every level of the food chain. Moreover, recently, airborne microplastic particles have been shown to reach and potentially damage respiratory systems. Microplastics and nanoplastics have been shown to cause increased oxidative stress, inflammation, altered metabolism leading to cellular damage, which ultimately affects tissue and organismal homeostasis in numerous animal species and human cells. However, the full impact of these plastic particles on living organisms is not completely understood. The ability of MPs/NPs to carry contaminants, toxic chemicals, pesticides, and bioactive compounds, such as endocrine disrupting chemicals, present an additional risk to animal and human health. This review will discusses the current knowledge on pathways by which microplastic and nanoplastic particles impact reproduction and reproductive behaviors from the level of the whole organism down to plastics-induced cellular defects, while also identifying gaps in current knowledge regarding mechanisms of action. Furthermore, we suggest that the nematode Caenorhabditis elegans provides an advantageous high-throughput model system for determining the effect of plastic particles on animal reproduction, using reproductive behavioral end points and cellular readouts.

Microplastics and Their Impact on Reproduction—Can we Learn From the C. elegans Model?

A key challenge of mixture toxicity testing is that a multitude of substances with even more combinations need to be tested in a broad dose range. Consequently testing in rodent bioassays, the current gold standard of toxicity testing, is hardly feasible. High-throughput compatible cell culture systems, however, suffer from limitations with respect to toxicokinetics, tissue interactions, and compensatory mechanisms. Therefore, simple organisms like the nematode Caenorhabditis elegans, combining relevant advantages of complex in vivo and fast in vitro assays might prove highly valuable within a testing strategy for mixtures. To investigate the comparability between results obtained with C. elegans and traditional rodent assays, we used five azole fungicides as well investigated model substances. Our findings suggest that azoles act additively in C. elegans which is in line with previous results in rats. Additionally, we show that toxicokinetics are one important factor for the differences in the relative toxicity of the azoles in both species. Importantly, we also demonstrate that in contrast to most rodent in vivo studies, C. elegans assays provide well-defined concentration-response relationships which are a very good basis for the prediction of mixture effects. We conclude that C. elegans may be an appropriate model for mixture toxicity testing at least within a first step to identify and prioritize relevant mixtures for further testing.

Caenorhabditis elegans As a Promising Alternative Model for Environmental Chemical Mixture Effect Assessment-A Comparative Study.

Summary Growth and offspring count are two commonly determined toxicological endpoints for chemical- or gene-induced developmental and reproductive effects in Caenorhabditis elegans. Here, we present a protocol for a 96 h, medium-throughput assay, assessing both endpoints quantitatively within an automated framework using open-source software. The assay utilizes whole 96-well fluorescence images taken with a high-content screening system. Alternatively, conventional fluorescence images can also be utilized with only a few adjustments. For complete details on the use and execution of this protocol, please refer to Wittkowski et al. (2019) .

A quantitative medium-throughput assay to measure Caenorhabditis elegans development and reproduction.

The future of risk assessment cannot neglect to consider the vast literature produced through the application of new approach methodologies (NAMs). This, though, constitutes a challenge for the risk assessor, as the production in this context is huge and heterogeneous both for the methods applied and the standardisation and quality of the results. The integration of results from NAMs is hence only feasible under some degree of automation of the risk assessment workflow, specifically for searching, extracting and integrating such results in “AOP-like” knowledge networks (AOP – Adverse Outcome Pathway). Artificial intelligence (AI) with its state-of-the-art methods and tools is the most promising source for help among modern technologies supporting automation of manual tasks. Within the broader context of investigating possible applications of AI to achieve this goal, the present paper illustrates an evaluation framework to quantitatively assess these tools and methods and, in turn, support the selection of the most promising among them for a (at least partial) automation of the overall workflow. It also provides a survey of the state-of-the-art tools and methods identified at present which can then be assessed for specific use cases with the help of the introduced evaluation framework. 

Paul Wittkowski

Papers

Caenorhabditis elegans As a Promising Alternative Model for Environmental Chemical Mixture Effect Assessment-A Comparative Study.

A quantitative medium-throughput assay to measure Caenorhabditis elegans development and reproduction.

Review of state‐of‐the‐art AI tools and methods for screening, extracting and evaluating NAMs literature in the context of chemical risk assessment